C

Calories

Included 2388 patients requiring nutritional support in England who were admitted to the ICU within the past 36 hours and expected to remain for at least 3 days

Randomized patients to either 25 kcal/kg of parenteral or enteral nutrition for 5 total days (or until transition to exclusive oral feeding or ICU discharge)

This was a very pragmatic trial — decisions regarding feeding formulation/composition, threshold for gastric residuals, use of prokinetic agents, and other factors were at the discretion of the clinicians

Primary endpoint (30-day mortality) was not different between parenteral and enteral nutrition (33.1% vs. 34.2%, p=0.57)

The study met 90% power to detect a 20% relative risk reduction in 30-day mortality

Unlike in previous trials, parenteral nutrition was not associated with a greater risk of “infectious complications” per patient (0.22 vs. 0.21, p=0.72), although because the trial was not blinded, there is risk for bias

There were no differences in SOFA scores, length of stay, or 90-day mortality

Parenteral nutrition was associated with slightly higher mean calories per day (21.3 vs. 18.5 kcal/kg, no p value); the majority of patients did not meet the 25 kcal/kg goal

Enteral nutrition was associated with more “clinically significant hypoglycemia (based on clinical judgment, 3.7% vs. 6.2%, p=0.006), although “serious” hypoglycemia was not different (0.4% vs. 0.3%)

Enteral nutrition was associated with more vomiting (8.4% vs. 16.2%, p<0.001) and prokinetic use (2.2% vs. 35.6%), although there was no difference in the rate of aspiration events or pneumonia

As mentioned by the authors, there may be a dose-dependent risk of infection with parenteral nutrition. Given that most patients did not achieve the goal number of calories, the risk of infection with parenteral nutrition may have been minimized.

No cost analysis was done, which has been shown to be a major difference in other trials (eg, EPaNIC)

TBL

Among a heterogeneous ICU patient population, there was no difference in mortality between exclusive enteral and parenteral nutrition support.

“Treatment” consisted of lowering systolic BP by 10-25% within the first 24 hours (no lower than 126/80) and a goal of < 140/90 mmHg within 7 days. An algorithm using an ACE inhibitor, calcium channel blocker, and diuretic was used to manage antihypertensive regimens.

“Control” consisted of no antihypertensive medications during hospitalization, but would be able to resume antihypertensives following hospital discharge

Primary endpoint (14-day mortality or major disability) was not different between “treatment” and “control” (33.6% vs. 33.6%, p=0.98)

The trial was adequately powered to detect a 5% absolute difference in the primary endpoint

At 3 months, there was no difference in mortality or major disability (25.2% vs. 25.3%, p=0.93)

Based on the NIHSS scores (median 4), patient in this trial had less severe symptoms at baseline compared to other stroke trials (eg, NINDS trial median of 14 — higher number indicating worse severity). This may limit the external validity of the trial for patients with more severe stroke.

Despite a low percentage of patients with embolic stroke (about 5%), use of heparin or low molecular weight heparin was common (33.4%), which is reflective of the typical practice in China (again, a possible risk to external validity for US-based patients)

TBL

Among patients with ischemic stroke who do not receive TPA, more aggressive blood pressure reduction during hospitalization does not improve mortality or major disability.

Chest

Excluded patients with dialysis-dependent renal failure or intracranial hemorrhage
Randomized to 6% HES 130/0.4 (Voluven) or 0.9% normal saline for the duration of the patient’s ICU stay. In patients requiring more than 50 mL/kg/day, open-label saline was used

Primary endpoint (90-day all-cause mortality) was not different between HES and saline (18% vs. 17%, p=0.26)

This study was powered to detect an absolute difference of 3% in mortality

Chip

Included 1369 pediatric ICU patients (age 36 weeks – 16 years) with an arterial catheter, mechanical ventilation, AND vasoactive drugs after an injury, major surgery, or critical illness. About 60% of patients were less than 1 year old and about 60% of patients were admitted following cardiac surgery.

Primary endpoint (number of days alive and free from mechanical ventilation at 30-days) was not different between tight and conventional glycemic control groups (mean -0.36 days [95% CI -0.42 to 1.14])

There was no difference in 12-month mortality

Renal replacement therapy was more common with conventional therapy (13.5% vs. 8.9%, OR 0.63 [95% CI 0.45-0.89]); however, this secondary endpoint is at risk for a type-I error due to the number of secondary endpoints analyzed

Among the entire cohort, hypoglycemia was associated with an increase in mortality (11.1% vs. 4.4%, p=0.001)

Conventional therapy was associated with a longer hospital length of stay (by 13.5 days) and higher costs (by $13,120) in non-cardiac surgery patients. Cardiac surgery patients had no difference in length of stay or costs.

Hyperglycemia was uncommon in the conventional group. At 10 days after randomization, mean (SD) blood glucose values were 105 (21) mg/dL vs. 112 (33) mg/dL (p=0.041). Although significantly different, it seems unlikely that a mean difference of about 7 mg/dL would have a profound clinical impact. It is not known whether tight glycemic control would have an effect on the primary endpoint among patients with true hyperglycemia (eg, above 180 mg/dL)

Only about 7% of those assessed for eligibility met study criteria, which reduces external validity. However, the study criteria selected the “sickest” type of patients in a pediatric ICU, presumably the subgroup of patients that would be most likely to benefit from the study treatment.

TBL

Among critically ill pediatric patients, tight glycemic control did not reduce 30-day mortality or duration of mechanical ventilation, but it did increase the risk of hypoglycemia. For unclear reasons, non-cardiac surgery patients had a shorter 12-month hospital length of stay and hospital cost. The study is limited by a lack of hyperglycemia in the control group

New infections (primarily UTI) were more common with fludrocortisone than placebo (21.6% vs. 14%, p=0.02, NNH 13)

This study helped clarify the role of intensive glucose control in septic shock (van den Berghe and NICE-SUGAR included all types of ICU patients), and the role of fludrocortisone as an adjunct to hydrocortisone in septic shock (Annane 2002 vs. CORTICUS)

TBL

Among patients with septic shock receiving hydrocortisone, neither intensive glucose control nor fludrocortisone improved mortality. Intensive glucose control was associated with a higher incidence of hypoglycemia and fludrocortisone with a higher incidence of new infections.

Primary endpoint (28-day mortality among non-responders) was not different between hydrocortisone or placebo (39.2% vs. 36.1%, p=0.69)

Mortality among responders was not different (28.8% vs. 28.7%, p=1.00)
Time to reversal of shock (SBP > 90 mmHg without vasopressors for at least 24 hrs) was quicker with hydrocortisone (3.3 vs. 5.8 days) for both responders and non-responders
Patients receiving hydrocortisone had a higher incidence of new infections occurring 48+ hrs after study drug (OR 1.37, 95% CI 1.05 to 1.79), hyperglycemia, and hypernatremia
Study was underpowered for the primary endpoint (only enrolling 499 of a projected 800 for adequate power). Given the lack of effect seen, study is at high risk for type-II error

TBL

Hydrocortisone therapy did not improve outcomes among patients with septic shock (onset within 72 hours), although it did shorten the duration of vasopressor dependence.

TBL

Cristal

Included 2,857 patients requiring fluid resuscitation for hypovolemia (hypotension with low cardiac filling pressures and signs of hypoxia/hypoperfusion). Patients could NOT have received any form of fluid resuscitation in the ICU prior to the study enrollment.

Randomized patients to crystalloids or colloids. Investigators were non-blinded and allowed to select from a variety of fluid options. In the crystalloid group, normal saline was used in 85% of cases and Ringers lactate in 18%. In the colloid group, hydroxyethyl starch was used in 69% of patients, gelatins in 35%, albumin-4% in 6%, and albumin-20% in 14%. The dose of fluid was also at the discretion of the unblinded investigator.

Primary endpoint (28-day mortality) was not different between crystalloids and colloids (27.0% vs. 25.4%, p=0.26). The study was halted early due to futility — an additional 153 patients were planned based on the initial power calculation.

Appropriately, the authors conclude that the benefit in 90-day mortality is exploratory and requires further study

Colloids were associated with a modest reduction in days alive without mechanical ventilation in the first 7 days (2.1 vs. 1.8 days, p=0.01) and 28 days (14.6 vs. 13.5, p=0.01)

Colloids were associated with a modest reduction in days alive without vasopressors in the first 7 days (5 vs. 4.7 days, p=0.04) and 28 days (16.2 vs. 15.2 days, p=0.03)

Within the first 7 days, patients receiving crystalloids demonstrated a higher median cumulative fluid intake (3000 mL vs. 2000 mL, p<0.001). Because the trial was not blinded, the potency ratio (1:1.5) should be considered with caution.

Given the fact that about half of the patients had severe sepsis or septic shock, the median total fluid received in the first 7 days (3000 mL crystalloid) appears to be quite low, which questions the severity of hypovolemia in the patients

Unlike previous colloids or hetastarch trials, there was no difference between the two groups regarding blood transfusions or renal replacement therapy

Given the heterogeneity of the type of fluids used in this trial and the conflicting data with previous trials (SAFE, CHEST, 6S, and more), the topic of crystalloids versus colloids remains controversial

TBL

In a heterogeneous ICU population with hypovolemia, there was no difference in 28-day mortality between crystalloids and colloids. Colloids did demonstrate benefit in duration of mechanical ventilation, vasopressor use, and 90-day mortality, although these were secondary endpoints that are conflicting with previous literature and deserve further study.

On day 1, about 90% of patients received double coverage with a B-lactam plus either quinolone or aminoglycoside

In subgroup analysis, there was no difference in recurrence for MRSA, but there was a higher incidence of recurrence (40.6% vs. 25.4%) for nonfermenting gram negative rods (Pseudomonas, Acinetobacter, Stenotrophomonas)

Study may have been underpowered (power estimate of 40% mortality, actual rate closer to 20%)

TBL

Among patients with late-onset VAP or early-onset VAP with recent antibiotic exposure, 8-days was non-inferior to 15-days of appropriate antibiotic therapy for mortality and pneumonia recurrence. In patients with certain non-fermenting gram negatives, a 15-day course may be more appropriate.